New targets for HIV therapy

In a pair of studies published last year, researchers across Europe used computer simulations to make major advances in our understanding of HIV. Taking advantage of distributed computing networks, they simulated key processes and molecular interactions in the life cycle of the virus, identifying new targets for drug therapy.

In order to invade and infect cells, the HIV virus uses proteins, the molecular machinery of life. Like many human-built machines, proteins accomplish their tasks by being a certain shape; wheels would be much less efficient if they weren’t round, while the specific shape of a key enables it to open a particular lock. A protein’s shape is determined by interactions between the atoms that make it up. Understanding this shape can tell us something about how the protein works or, in the case of an HIV protein, how to stop it from working.

Scientists can measure the shape of a protein using a technique called crystallography, but this only captures a snapshot, freezing a single moment of what is actually a dynamic, variable process. To get an idea of how the shape changes over time, scientists simulate the interactions between the thousands of atoms that make up a protein. The sheer number of interactions makes this an enormous task demanding immense computational power. To run these simulations cost-effectively, researchers use a technique known as grid computing, which combines the processing power from the idle computers of volunteers around the world to create a virtual supercomputer.

One of the questions that’s been tackled using this technology is how newly-formed HIV particles in a cell mature and infect new cells. HIV and other retroviruses produce the proteins they need in a single connected stretch, like a string of pearls, and these proteins have to be cut free before they become active. A special protein called a protease acts like a pair of scissors, cutting the string of pearls, but a problem arises since the protease itself is part of the protein necklace. To make matters worse, just as a scissors needs two blades, the protease only works if two copies come together to act in concert. In other words, for HIV particles to become active and infectious, two strings of proteins have to come together in just the right way for the proteases in them to line up together and snip themselves out, after which they can cut the other proteins free.

Researchers from labs in Germany and Spain used a network called the GPUGRID to understand this complex dance; by combining the power of thousands of volunteers’ computers, they simulated the interactions of all 40,000 atoms in the protease for 400 billionths of a second – a mere fraction of an instant, but long enough to see what happens. In a paper published in the journal PNAS, the team described how the protein contorts to thread one of its ends between the scissor blades and cut itself free. They believe that blocking this crucial step might be a fruitful new strategy in treating HIV.

Once the protease is free, it cuts the other proteins loose. One of these, a “reverse transcriptase”, is the target of many drugs used to treat HIV. In another study, the Spanish lab cooperated with a group in the UK to investigate how these drugs bind to the protein and block its activity. The protein, which copies RNA into DNA, is shaped like an open hand; it works by closing the “thumb” and “fingers” around a RNA molecule to grip it and make a copy. Scientists believe that the drug nestles into the crook of the “thumb”, preventing the protein from working by locking the “hand” into an open position.

The team tested this idea using a network of computers called TeraGRID. In most of their simulations, the drug forced the hand to stay open, but in one case the hand was able to close despite the drug. Even though the thumb folded over the palm in this simulation, the drug forced it to touch the fingers in a different place than it would have otherwise. The researchers suspect that the change in contact between the thumb and fingers affects which bits of RNA the protein recognizes and grips, interfering with its ability to function properly. Based on their new understanding of this process, they suggest that drugs could be designed to force the protein into the non-functional closed state, providing a new target for anti-retroviral therapy.

By harnessing the power of grid computing, scientists have been able to study the development of HIV in greater detail than ever before. Understanding these key molecular processes can help us create new drugs and target existing ones more effectively, offering increased hope to people afflicted with this disease.

RefsSadiq SK, Noé F, & De Fabritiis G (2012). Kinetic characterization of the critical step in HIV-1 protease maturation. Proceedings of the National Academy of Sciences of the United States of America, 109 (50), 20449-54 PMID: 23184967

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5 thoughts on “New targets for HIV therapy”

A simple question: what is a retrovirus (compared to a virus)?
Also, are these drugs that could help at later stages, or only at the beginning before the scissors have done much scissoring?
And one more. Could you, in principle (clearly not in practice), cure someone of HIV by examining all their blood under a microscope and removing the HIV viruses? Are they even large enough to see with a microscope?

A (hopefully!) simple answer: a retrovirus is a kind of RNA virus — that is, a virus that uses RNA instead of DNA for its genetic material. Retroviruses are different from other RNA viruses (called riboviruses) because they copy their RNA back into DNA (hence “retro”) when infecting a cell; other RNA viruses just use the RNA directly.

Yes, drugs targeting the scissors could also be used at later stages. The “scissoring” takes place whenever HIV infects a cell, which is constantly happening in someone who has HIV. The virus infects a cell, makes the proteins needed to replicate itself (this is where the scissors come in), replicates and then bursts out of the cell, killing it. The new virus particles then go on to infect other cells. A drug that could block the scissors protein would interfere with the virus’ replication early in its cycle. This isn’t the same as saying “early in the infection”, since HIV is always replicating in someone who is HIV+.

In principle, you could cure someone by removing all of the HIV viruses from their system and getting rid of any infected cells (that are about to release newly replicated particles). One major problem, though, is that the virus isn’t just in the blood; it also gets into different tissues (including the brain). And no, you can’t see them with a (normal) microscope, but they are visible with an electron microscope.

Sorry, I just realized that I never replied to this comment — I thought I had! To answer your question, RNA is a kind of genetic material. RNA molecules are similar to DNA but have important differences. In most familiar creatures (plants, animals, bacteria, etc), a gene encoded in the DNA gets translated into RNA which is then used to make a protein. However, some viruses use RNA directly as their genetic material (ie, in place of DNA).